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Abstract

Brown adipose cells are specialized to dissipate chemical energy in the form of heat, as a physiological defence against cold and obesity1. PRDM16 (PR domain containing 16) is a 140 kDa zinc finger protein that robustly induces brown fat determination and differentiation2. Recent data suggests that brown fat cells arise in vivo from a Myf5-positive, myoblastic lineage by the action of PRDM16 (ref. 3); however, the molecular mechanisms responsible for this developmental switch is unclear. Here we show that PRDM16 forms a transcriptional complex with the active form of C/EBP-β (also known as LAP), acting as a critical molecular unit that controls the cell fate switch from myoblastic precursors to brown fat cells. Forced expression of PRDM16 and C/EBP-β is sufficient to induce a fully functional brown fat program in naive fibroblastic cells, including skin fibroblasts from mouse and man. Transplantation of fibroblasts expressing these two factors into mice gives rise to an ectopic fat pad with the morphological and biochemical characteristics of brown fat. Like endogenous brown fat, this synthetic brown fat tissue acts as a sink for glucose uptake, as determined by positron emission tomography with fluorodeoxyglucose. These data indicate that the PRDM16–C/EBP-β complex initiates brown fat formation from myoblastic precursors, and may provide opportunities for the development of new therapeutics for obesity and type-2 diabetes.

Acknowledgements

We are grateful to S. R. Farmer, J. Rheinwald and P. F. Johnson for providing cells and other reagents, R. Gupta for his critical comments on the manuscript, and J. Y. Choi and E. Naseri for their assistance. S.K. is supported by AHA scientist development grant (0930125N). P.S. is supported by a National Institutes of Health (NIH) grant (DK081605). This work was supported by grants from the Picower Foundation and the NIH (DK31405) to B.M.S., NIH HG3456 and GM67945 to S.P.G., and NIH/NCRR shared instrumentation grant S10-RR-023010.

Author Contributions S.K. and B.M.S. conceived and designed the experiments. S.K., K.K. and E.L. performed the experiments. All of the authors analysed the data. S.K. and B.M.S. wrote the paper.

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Editorial Summary

Brown fat and obesity

Brown fat tissue can act to counteract obesity, by burning calories to produce heat, whereas white fat acts as an energy store. Bruce Spiegelman and colleagues reported in Nature last year that brown fat cells are closely related to skeletal muscle, and that the protein PRDM16 can instruct muscle stem cells to become brown fat cells. Now from the same lab comes the finding that PRDM16 works together with C/EBP-β and that expression of this transcriptional unit is sufficient to induce a fully functional brown fat in naive fibroblasts. Transplantation of such fibroblasts into mice creates a brown fat pad that acts as a sink for glucose. This work could lead to new approaches to controlling metabolic disorders such as obesity and type-2 diabetes.